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Fig. 1 | Genome Medicine

Fig. 1

From: Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework

Fig. 1

Assembly of variant controls to set readout thresholds for normal and abnormal functions. Readout values across multiple specific instances of the same type can be plotted for any tested variant that reaches a likely benign/benign (LB/B) or likely pathogenic/pathogenic (LP/P) classification without PS3 or BS3 criteria. Each point on the plot represents the assay readout from a specific instance of an assay for the variant listed on the x-axis. Multiple points for the same variant indicate that the variant was tested in multiple specific instances of the same general class of assay. In this example, all LB/B variant controls (B1–B6) had readouts above 60%, with the exception of variant B6. When setting a readout threshold above which the readout is considered normal function, curators may draw this threshold at 60% and consider B6 to have an indeterminate readout. All LP/P variant controls (P1–P5) had readouts below 30%, with the exception of one specific instance for variant P1. With just 1 LB/B control variant with an indeterminate readout from a total of 11 variant controls (6 LB/B and 5 LP/P), PS3_moderate can be applied to variants with a readout indicating abnormal function and BS3_moderate can be applied to variants with a readout indicating normal function (see Additional file 1: Table S2). Variants of uncertain significance (VUS) tested on the same class of assay are plotted in the middle of the graph (indicated by light gray shading). VUS1 has an assay readout in the range of LB/B controls and would be above the threshold for normal function, so BS3_moderate could be applied. VUS3 has an assay readout consistent with LP/P control variants, below the threshold for abnormal function, so PS3_moderate could be applied. VUS2 has an indeterminate assay readout, so neither PS3_moderate nor BS3_moderate can be applied for this variant

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